Biliary Findings and the Neoplastic Potential of Branch Duct Intraductal Papillary Mucinous Neoplasm

Abstract

Mucinous cysts including intraductal papillary mucinous neoplasms (IPMNs) are the only readily detectable precursors of pancreas cancer.1Canto M.I. Goggins M. Hruban R.H. et al.Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study.Clin Gastroenterol Hepatol. 2006; 4 (quiz 665): 766-781Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar, 2Topazian M. Enders F. Kimmey M. et al.Interobserver agreement for EUS findings in familial pancreatic-cancer kindreds.Gastrointest Endosc. 2007; 66: 62-67Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar Akin to colonic polyps, they proceed through a sequence of dysplastic changes en route to carcinoma. Nevertheless, in contrast to polypectomy, resection of cysts is associated with higher morbidity. Thus, identification of pancreatic cysts with malignant potential is a high priority. Intensive work has identified morphologic, biochemical, and genetic features that predict neoplastic risk in pancreatic cysts. In this issue of Clinical Gastroenterology and Hepatology, Matsuzaki et al3Matsuzaki J. Suzuki H. Okuda S. et al.Biliary findings assist in predicting enlargement of intraductal papillary mucinous neoplasms of the pancreas.Clin Gatroenterol Hepatol. 2013; 11: 548-554Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar propose that the features of the biliary tree in addition to characteristics of the cyst may predict neoplastic progression of the cyst. In their large cohort, gallbladder adenomyomatosis and cholelithiasis were associated with branch duct (BD) IPMNs. Long-term surveillance with magnetic resonance cholangiopancreatography indicated that cyst diameter greater than 17 mm, adenomyomatosis, and common bile duct diameter less than 5.5 mm predicted enlargement of BD-IPMN. Their work also suggests a novel mechanism by which IPMNs develop as well as a theoretical approach to treat them. They propose that reflux of bile into the pancreatic duct may promote cyst growth, and biliary sphincterotomy may prevent this.IPMNs are saccular and cystic dilatations of the main or side branches of the pancreatic duct. The neoplastic potential of IPMN is harbored in the rind of the cyst, which is composed of a proliferative, mucin-producing columnar epithelium from which the eponymous papillary projections originate.4Adsay N.V. Conlon K.C. Zee S.Y. et al.Intraductal papillary-mucinous neoplasms of the pancreas: an analysis of in situ and invasive carcinomas in 28 patients.Cancer. 2002; 94: 62-77Crossref PubMed Scopus (249) Google Scholar As genetic mutations accumulate in the epithelial cells, the cyst grows, and its neoplastic lining thickens. Mural nodules initially protrude into the lumen and eventually involute into the pancreatic parenchyma as solid carcinoma. Pancreatic surgery may be used to resect cysts with worrisome features, but it is complicated by fistulas, infections, and gastroparesis in 20%–50% of cases even at centralized referral centers.5Matsuoka L. Selby R. Genyk Y. The surgical management of pancreatic cancer.Gastroenterol Clin North Am. 2012; 41: 211-221Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Furthermore, only a small fraction of cystic lesions, especially the BD-IPMNs, become malignant. Large series have demonstrated that less than 25% of BD-IPMNs harbor carcinoma, and less than 15% without mural nodules will progress within 5 years of follow-up.6Tanno S. Nakano Y. Nishikawa T. et al.Natural history of branch duct intraductal papillary-mucinous neoplasms of the pancreas without mural nodules: long-term follow-up results.Gut. 2008; 57: 339-343Crossref PubMed Scopus (199) Google Scholar, 7Rodriguez J.R. Salvia R. Crippa S. et al.Branch-duct intraductal papillary mucinous neoplasms: observations in 145 patients who underwent resection.Gastroenterology. 2007; 133 (quiz 309–310): 72-79Abstract Full Text Full Text PDF PubMed Scopus (363) Google ScholarThus, 2 international consensus conferences have aimed to identify which BD-IPMNs have the greatest malignant potential.8Tanaka M. Chari S. Adsay V. et al.International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas.Pancreatology. 2006; 6: 17-32Abstract Full Text PDF PubMed Scopus (1633) Google Scholar, 9Tanaka M. Fernández-del Castillo C. Adsay V. et al.International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas.Pancreatology. 2012; 12: 183-197PubMed Scopus (1666) Google Scholar High-risk features include a size greater than 3 cm, mural nodules, and a dilated main pancreatic duct. Surgical resection is recommended for cysts with these characteristics and surveillance imaging for the remainder. Recent work has also shown that increasing cyst diameter over time is a strong predictor of subsequent malignant degeneration.10Kang M.J. Jang J.Y. Kim S.J. et al.Cyst growth rate predicts malignancy in patients with branch duct intraductal papillary mucinous neoplasms.Clin Gastroenterol Hepatol. 2011; 9: 87-93Abstract Full Text Full Text PDF PubMed Scopus (156) Google ScholarMatsuzaki et al identified additional risk factors for malignant transformation of BD-IPMNs, those that predict cyst growth. Their findings further emphasize that cyst size is a critical feature of high-risk lesions. They suggest that mural nodules and wall thickening are not predictors but rather consequences of malignant transformation. Their findings are consistent with histologic analysis of mural nodules that shows dysplasia.11Buxbaum J.L. Jhala N.C. Christein J.D. et al.Oncocytic intraductal papillary mucinous neoplasm with carcinomatous degeneration.Gastrointest Endosc. 2012; 75: 898-899Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Their most provocative findings are that bile duct diameter and gallbladder adenomyomatosis are correlated with pancreatic cyst behavior.Pancreaticobiliary maljunction (PBM) occurs when a long common channel or aberrant connection between the pancreas and bile ducts abrogates the sphincter of Oddi's ability to prevent reciprocal regurgitation of bile into the pancreatic duct and pancreatic juice into the bile duct.12Kamisawa T. Ando H. Suyama M. et al.Japanese clinical practice guidelines for pancreaticobiliary maljunction.J Gastroenterol. 2012; 47: 731-759Crossref PubMed Scopus (114) Google Scholar PBM is subclassified by the presence of a dilated (>10 mm) vs normal-caliber bile duct. Reciprocal or bidirectional reflux of bile and pancreatic juice has been correlated with a number of problems. Regurgitation of pancreatic juice into the biliary tree (pancreaticobiliary reflux) is associated with choledochal cyst as well as an increased risk of gallbladder and bile duct dysplasia and carcinoma.13Tanno S. Obara T. Maguchi H. et al.Association between anomalous pancreaticobiliary ductal union and adenomyomatosis of the gall-bladder.J Gastroenterol Hepatol. 1998; 13: 175-180Crossref PubMed Scopus (24) Google Scholar It is postulated that noxious pancreatic juice results in a cycle of inflammation and regeneration conducive to dysplastic changes.14Sakamoto H. Mutoh H. Ido K. et al.Intestinal metaplasia in gallbladder correlates with high amylase levels in bile in patients with a morphologically normal pancreaticobiliary duct.Hum Pathol. 2009; 40: 1762-1767Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Reflux of bile into the pancreatic ducts (biliopancreatic reflux) is correlated with the occurrence of recurrent pancreatitis. Although the authors do not comment on the presence of PBM in the series, bidirectional reflux may result in pancreatitis and biliary dysplasia even in those with normal anatomy.14Sakamoto H. Mutoh H. Ido K. et al.Intestinal metaplasia in gallbladder correlates with high amylase levels in bile in patients with a morphologically normal pancreaticobiliary duct.Hum Pathol. 2009; 40: 1762-1767Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 15Kamisawa T. Amemiya K. Tu Y. et al.Clinical significance of a long common channel.Pancreatology. 2002; 2: 122-128Abstract Full Text PDF PubMed Scopus (71) Google Scholar In addition, although it is relatively rare, pancreatic carcinoma is 49.4 times more likely in those with PBM than in the overall Japanese population and has been reported to arise from IPMN.16Funabiki T. Matsubara T. Miyakawa S. et al.Pancreaticobiliary maljunction and carcinogenesis to biliary and pancreatic malignancy.Langenbecks Arch Surg. 2009; 394: 159-169Crossref PubMed Scopus (117) Google Scholar, 17Eriguchi N. Aoyagi S. Okuda K. et al.Carcinoma arising in the pancreas 17 years after primary excision of a choledochal cyst: report of a case.Surg Today. 2001; 31: 534-537Crossref PubMed Scopus (23) Google ScholarNonetheless, biliary tree and gallbladder anomalies were not frequently reported in endoscopic retrograde cholangiopancreatography or endoscopic ultrasound studies of IPMN.18Cellier C. Cuillerier E. Palazzo L. et al.Intraductal papillary and mucinous tumors of the pancreas: accuracy of preoperative computed tomography, endoscopic retrograde pancreatography and endoscopic ultrasonography, and long-term outcome in a large surgical series.Gastrointest Endosc. 1998; 47: 42-49Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar In addition, patients with chronic pancreatitis can have both dilated side branches, which are often impossible to distinguish from BD-IPMN, and bile duct dilatation caused by extrinsic compression from pancreas fibrosis.19Kahl S. Zimmermann S. Genz I. et al.Risk factors for failure of endoscopic stenting of biliary strictures in chronic pancreatitis: a prospective follow-up study.Am J Gastroenterol. 2003; 98: 2448-2453Crossref PubMed Scopus (132) Google Scholar, 20Littenberg G. Afroudakis A. Kaplowitz N. Common bile duct stenosis from chronic pancreatitis: a clinical and pathologic spectrum.Medicine (Baltimore). 1979; 58: 385-412PubMed Google Scholar The inverse correlation between bile duct diameter and risk of pancreas cysts may be driven in part by the minimal neoplastic potential of pseudocysts. In addition, although it is plausible that chronic bile into the pancreas would cause dysplastic changes, this finding has only been confirmed in animal models.21Adachi T. Tajima Y. Kuroki T. et al.Bile-reflux into the pancreatic ducts is associated with the development of intraductal papillary carcinoma in hamsters.J Surg Res. 2006; 136: 106-111Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Finally, gallbladder adenomyomatosis that is characterized by muscularis mucosa hypertrophy and epithelial proliferation is not a definite premalignant lesion. However, it is thought to arise from chronic inflammation and high intraluminal pressure, which are both correlated with neoplastic change.13Tanno S. Obara T. Maguchi H. et al.Association between anomalous pancreaticobiliary ductal union and adenomyomatosis of the gall-bladder.J Gastroenterol Hepatol. 1998; 13: 175-180Crossref PubMed Scopus (24) Google ScholarThe findings of Matsuzaki et al bring up several questions that will catalyze further systematic investigation. They propose that the smaller-caliber bile ducts correlate with greater biliary hydrostatic pressure, which may favor biliopancreatic reflux and hence pancreatic cyst formation (Figure 1). This is particularly intriguing because it has previously been hypothesized that increased biliary hydrostatic pressure in those with PBM and normal bile duct size results in the transmission of pressure from the bile duct to the gallbladder. This has been proposed to account for the markedly increased incidence of gallbladder cancer in those with PBM and normal bile ducts, 36%, compared with 9% in those with PBM and large ducts.16Funabiki T. Matsubara T. Miyakawa S. et al.Pancreaticobiliary maljunction and carcinogenesis to biliary and pancreatic malignancy.Langenbecks Arch Surg. 2009; 394: 159-169Crossref PubMed Scopus (117) Google Scholar, 22Kamisawa T. Takuma K. Anjiki H. et al.Pancreaticobiliary maljunction.Clin Gastroenterol Hepatol. 2009; 7: S84-S88Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar In addition, the increased incidence of pancreatic cancer in those with PBM is predominantly found in those with a normal duct size.16Funabiki T. Matsubara T. Miyakawa S. et al.Pancreaticobiliary maljunction and carcinogenesis to biliary and pancreatic malignancy.Langenbecks Arch Surg. 2009; 394: 159-169Crossref PubMed Scopus (117) Google Scholar The research agenda might start with a review of the pancreas imaging of the cohort of patients followed by the Japanese Study Group on Pancreaticobiliary Maljunction to assess for BD-IPMNs.12Kamisawa T. Ando H. Suyama M. et al.Japanese clinical practice guidelines for pancreaticobiliary maljunction.J Gastroenterol. 2012; 47: 731-759Crossref PubMed Scopus (114) Google Scholar Endoscopic retrograde cholangiopancreatography to gauge pressure and biliopancreatic reflux in those with cystic lesions is a consideration, although dynamic magnetic resonance cholangiopancreatography may be a less invasive starting point.The authors suggest that endoscopic biliary sphincterotomy might impact the progression of BD-IPMNs. In patients with PBM, the sphincter of Oddi no longer prevents bidirectional reflux of bile and pancreatic juice. Nonetheless, sphincter of Oddi manometry shows dysfunction in patients with PBM, and sphincterotomy significantly improves their clinical course.23Guelrud M. Morera C. Rodriguez M. et al.Sphincter of Oddi dysfunction in children with recurrent pancreatitis and anomalous pancreaticobiliary union: an etiologic concept.Gastrointest Endosc. 1999; 50: 194-199Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar Further work to correlate biliary anomalies with IPMNs is needed before clinical studies of endoscopic or surgical therapy that are based on these propositions.Because of the bleak outcome of pancreas carcinoma, high morbidity of pancreas surgery, and high cost of intensive surveillance, several approaches are being investigated to assess which pancreatic cysts have malignant potential. Measurement of carcinoembyronic antigen levels and genetic analysis of the juice obtained by fine-needle aspiration are frequently performed.24Brugge W.R. Lewandrowski K. Lee-Lewandrowski E. et al.Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study.Gastroenterology. 2004; 126: 1330-1336Abstract Full Text Full Text PDF PubMed Scopus (1095) Google Scholar, 25Khalid A. Zahid M. Finkelstein S.D. et al.Pancreatic cyst fluid DNA analysis in evaluating pancreatic cysts: a report of the PANDA study.Gastrointest Endosc. 2009; 69: 1095-1102Abstract Full Text Full Text PDF PubMed Scopus (356) Google Scholar The passage of tiny scopes and confocal probes through fine-needle aspiration needles to enable direct visualization and microscopic assessment of the cyst lining is under active investigation.26Konda V.J. Aslanian H.R. Wallace M.B. et al.First assessment of needle-based confocal laser endomicroscopy during EUS-FNA procedures of the pancreas (with videos).Gastrointest Endosc. 2011; 74: 1049-1060Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 27Nakai Y. Iwashita T. Park D.H. et al.Diagnosis of pancreatic cysts: endoscopic ultrasound, through-the-needle confocal laser-induced endomicroscopy and cystoscopy trial (Detect Study).Gastrointest Endosc. 2012; 75: AB145-AB146Abstract Full Text Full Text PDF Google Scholar Nonetheless, careful analysis of cyst appearance, often during the initial radiographic or endosonographic (endoscopic ultrasound) analysis, is the least invasive and most straightforward means to characterize the adverse potential of these lesions. Although cyst size and morphology remain paramount considerations, the appearance of structures “in the neighborhood” of the cyst may harbor clues about future behavior as well as potential treatment. Mucinous cysts including intraductal papillary mucinous neoplasms (IPMNs) are the only readily detectable precursors of pancreas cancer.1Canto M.I. Goggins M. Hruban R.H. et al.Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study.Clin Gastroenterol Hepatol. 2006; 4 (quiz 665): 766-781Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar, 2Topazian M. Enders F. Kimmey M. et al.Interobserver agreement for EUS findings in familial pancreatic-cancer kindreds.Gastrointest Endosc. 2007; 66: 62-67Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar Akin to colonic polyps, they proceed through a sequence of dysplastic changes en route to carcinoma. Nevertheless, in contrast to polypectomy, resection of cysts is associated with higher morbidity. Thus, identification of pancreatic cysts with malignant potential is a high priority. Intensive work has identified morphologic, biochemical, and genetic features that predict neoplastic risk in pancreatic cysts. In this issue of Clinical Gastroenterology and Hepatology, Matsuzaki et al3Matsuzaki J. Suzuki H. Okuda S. et al.Biliary findings assist in predicting enlargement of intraductal papillary mucinous neoplasms of the pancreas.Clin Gatroenterol Hepatol. 2013; 11: 548-554Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar propose that the features of the biliary tree in addition to characteristics of the cyst may predict neoplastic progression of the cyst. In their large cohort, gallbladder adenomyomatosis and cholelithiasis were associated with branch duct (BD) IPMNs. Long-term surveillance with magnetic resonance cholangiopancreatography indicated that cyst diameter greater than 17 mm, adenomyomatosis, and common bile duct diameter less than 5.5 mm predicted enlargement of BD-IPMN. Their work also suggests a novel mechanism by which IPMNs develop as well as a theoretical approach to treat them. They propose that reflux of bile into the pancreatic duct may promote cyst growth, and biliary sphincterotomy may prevent this. IPMNs are saccular and cystic dilatations of the main or side branches of the pancreatic duct. The neoplastic potential of IPMN is harbored in the rind of the cyst, which is composed of a proliferative, mucin-producing columnar epithelium from which the eponymous papillary projections originate.4Adsay N.V. Conlon K.C. Zee S.Y. et al.Intraductal papillary-mucinous neoplasms of the pancreas: an analysis of in situ and invasive carcinomas in 28 patients.Cancer. 2002; 94: 62-77Crossref PubMed Scopus (249) Google Scholar As genetic mutations accumulate in the epithelial cells, the cyst grows, and its neoplastic lining thickens. Mural nodules initially protrude into the lumen and eventually involute into the pancreatic parenchyma as solid carcinoma. Pancreatic surgery may be used to resect cysts with worrisome features, but it is complicated by fistulas, infections, and gastroparesis in 20%–50% of cases even at centralized referral centers.5Matsuoka L. Selby R. Genyk Y. The surgical management of pancreatic cancer.Gastroenterol Clin North Am. 2012; 41: 211-221Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Furthermore, only a small fraction of cystic lesions, especially the BD-IPMNs, become malignant. Large series have demonstrated that less than 25% of BD-IPMNs harbor carcinoma, and less than 15% without mural nodules will progress within 5 years of follow-up.6Tanno S. Nakano Y. Nishikawa T. et al.Natural history of branch duct intraductal papillary-mucinous neoplasms of the pancreas without mural nodules: long-term follow-up results.Gut. 2008; 57: 339-343Crossref PubMed Scopus (199) Google Scholar, 7Rodriguez J.R. Salvia R. Crippa S. et al.Branch-duct intraductal papillary mucinous neoplasms: observations in 145 patients who underwent resection.Gastroenterology. 2007; 133 (quiz 309–310): 72-79Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar Thus, 2 international consensus conferences have aimed to identify which BD-IPMNs have the greatest malignant potential.8Tanaka M. Chari S. Adsay V. et al.International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas.Pancreatology. 2006; 6: 17-32Abstract Full Text PDF PubMed Scopus (1633) Google Scholar, 9Tanaka M. Fernández-del Castillo C. Adsay V. et al.International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas.Pancreatology. 2012; 12: 183-197PubMed Scopus (1666) Google Scholar High-risk features include a size greater than 3 cm, mural nodules, and a dilated main pancreatic duct. Surgical resection is recommended for cysts with these characteristics and surveillance imaging for the remainder. Recent work has also shown that increasing cyst diameter over time is a strong predictor of subsequent malignant degeneration.10Kang M.J. Jang J.Y. Kim S.J. et al.Cyst growth rate predicts malignancy in patients with branch duct intraductal papillary mucinous neoplasms.Clin Gastroenterol Hepatol. 2011; 9: 87-93Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar Matsuzaki et al identified additional risk factors for malignant transformation of BD-IPMNs, those that predict cyst growth. Their findings further emphasize that cyst size is a critical feature of high-risk lesions. They suggest that mural nodules and wall thickening are not predictors but rather consequences of malignant transformation. Their findings are consistent with histologic analysis of mural nodules that shows dysplasia.11Buxbaum J.L. Jhala N.C. Christein J.D. et al.Oncocytic intraductal papillary mucinous neoplasm with carcinomatous degeneration.Gastrointest Endosc. 2012; 75: 898-899Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Their most provocative findings are that bile duct diameter and gallbladder adenomyomatosis are correlated with pancreatic cyst behavior. Pancreaticobiliary maljunction (PBM) occurs when a long common channel or aberrant connection between the pancreas and bile ducts abrogates the sphincter of Oddi's ability to prevent reciprocal regurgitation of bile into the pancreatic duct and pancreatic juice into the bile duct.12Kamisawa T. Ando H. Suyama M. et al.Japanese clinical practice guidelines for pancreaticobiliary maljunction.J Gastroenterol. 2012; 47: 731-759Crossref PubMed Scopus (114) Google Scholar PBM is subclassified by the presence of a dilated (>10 mm) vs normal-caliber bile duct. Reciprocal or bidirectional reflux of bile and pancreatic juice has been correlated with a number of problems. Regurgitation of pancreatic juice into the biliary tree (pancreaticobiliary reflux) is associated with choledochal cyst as well as an increased risk of gallbladder and bile duct dysplasia and carcinoma.13Tanno S. Obara T. Maguchi H. et al.Association between anomalous pancreaticobiliary ductal union and adenomyomatosis of the gall-bladder.J Gastroenterol Hepatol. 1998; 13: 175-180Crossref PubMed Scopus (24) Google Scholar It is postulated that noxious pancreatic juice results in a cycle of inflammation and regeneration conducive to dysplastic changes.14Sakamoto H. Mutoh H. Ido K. et al.Intestinal metaplasia in gallbladder correlates with high amylase levels in bile in patients with a morphologically normal pancreaticobiliary duct.Hum Pathol. 2009; 40: 1762-1767Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Reflux of bile into the pancreatic ducts (biliopancreatic reflux) is correlated with the occurrence of recurrent pancreatitis. Although the authors do not comment on the presence of PBM in the series, bidirectional reflux may result in pancreatitis and biliary dysplasia even in those with normal anatomy.14Sakamoto H. Mutoh H. Ido K. et al.Intestinal metaplasia in gallbladder correlates with high amylase levels in bile in patients with a morphologically normal pancreaticobiliary duct.Hum Pathol. 2009; 40: 1762-1767Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 15Kamisawa T. Amemiya K. Tu Y. et al.Clinical significance of a long common channel.Pancreatology. 2002; 2: 122-128Abstract Full Text PDF PubMed Scopus (71) Google Scholar In addition, although it is relatively rare, pancreatic carcinoma is 49.4 times more likely in those with PBM than in the overall Japanese population and has been reported to arise from IPMN.16Funabiki T. Matsubara T. Miyakawa S. et al.Pancreaticobiliary maljunction and carcinogenesis to biliary and pancreatic malignancy.Langenbecks Arch Surg. 2009; 394: 159-169Crossref PubMed Scopus (117) Google Scholar, 17Eriguchi N. Aoyagi S. Okuda K. et al.Carcinoma arising in the pancreas 17 years after primary excision of a choledochal cyst: report of a case.Surg Today. 2001; 31: 534-537Crossref PubMed Scopus (23) Google Scholar Nonetheless, biliary tree and gallbladder anomalies were not frequently reported in endoscopic retrograde cholangiopancreatography or endoscopic ultrasound studies of IPMN.18Cellier C. Cuillerier E. Palazzo L. et al.Intraductal papillary and mucinous tumors of the pancreas: accuracy of preoperative computed tomography, endoscopic retrograde pancreatography and endoscopic ultrasonography, and long-term outcome in a large surgical series.Gastrointest Endosc. 1998; 47: 42-49Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar In addition, patients with chronic pancreatitis can have both dilated side branches, which are often impossible to distinguish from BD-IPMN, and bile duct dilatation caused by extrinsic compression from pancreas fibrosis.19Kahl S. Zimmermann S. Genz I. et al.Risk factors for failure of endoscopic stenting of biliary strictures in chronic pancreatitis: a prospective follow-up study.Am J Gastroenterol. 2003; 98: 2448-2453Crossref PubMed Scopus (132) Google Scholar, 20Littenberg G. Afroudakis A. Kaplowitz N. Common bile duct stenosis from chronic pancreatitis: a clinical and pathologic spectrum.Medicine (Baltimore). 1979; 58: 385-412PubMed Google Scholar The inverse correlation between bile duct diameter and risk of pancreas cysts may be driven in part by the minimal neoplastic potential of pseudocysts. In addition, although it is plausible that chronic bile into the pancreas would cause dysplastic changes, this finding has only been confirmed in animal models.21Adachi T. Tajima Y. Kuroki T. et al.Bile-reflux into the pancreatic ducts is associated with the development of intraductal papillary carcinoma in hamsters.J Surg Res. 2006; 136: 106-111Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Finally, gallbladder adenomyomatosis that is characterized by muscularis mucosa hypertrophy and epithelial proliferation is not a definite premalignant lesion. However, it is thought to arise from chronic inflammation and high intraluminal pressure, which are both correlated with neoplastic change.13Tanno S. Obara T. Maguchi H. et al.Association between anomalous pancreaticobiliary ductal union and adenomyomatosis of the gall-bladder.J Gastroenterol Hepatol. 1998; 13: 175-180Crossref PubMed Scopus (24) Google Scholar The findings of Matsuzaki et al bring up several questions that will catalyze further systematic investigation. They propose that the smaller-caliber bile ducts correlate with greater biliary hydrostatic pressure, which may favor biliopancreatic reflux and hence pancreatic cyst formation (Figure 1). This is particularly intriguing because it has previously been hypothesized that increased biliary hydrostatic pressure in those with PBM and normal bile duct size results in the transmission of pressure from the bile duct to the gallbladder. This has been proposed to account for the markedly increased incidence of gallbladder cancer in those with PBM and normal bile ducts, 36%, compared with 9% in those with PBM and large ducts.16Funabiki T. Matsubara T. Miyakawa S. et al.Pancreaticobiliary maljunction and carcinogenesis to biliary and pancreatic malignancy.Langenbecks Arch Surg. 2009; 394: 159-169Crossref PubMed Scopus (117) Google Scholar, 22Kamisawa T. Takuma K. Anjiki H. et al.Pancreaticobiliary maljunction.Clin Gastroenterol Hepatol. 2009; 7: S84-S88Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar In addition, the increased incidence of pancreatic cancer in those with PBM is predominantly found in those with a normal duct size.16Funabiki T. Matsubara T. Miyakawa S. et al.Pancreaticobiliary maljunction and carcinogenesis to biliary and pancreatic malignancy.Langenbecks Arch Surg. 2009; 394: 159-169Crossref PubMed Scopus (117) Google Scholar The research agenda might start with a review of the pancreas imaging of the cohort of patients followed by the Japanese Study Group on Pancreaticobiliary Maljunction to assess for BD-IPMNs.12Kamisawa T. Ando H. Suyama M. et al.Japanese clinical practice guidelines for pancreaticobiliary maljunction.J Gastroenterol. 2012; 47: 731-759Crossref PubMed Scopus (114) Google Scholar Endoscopic retrograde cholangiopancreatography to gauge pressure and biliopancreatic reflux in those with cystic lesions is a consideration, although dynamic magnetic resonance cholangiopancreatography may be a less invasive starting point. The authors suggest that endoscopic biliary sphincterotomy might impact the progression of BD-IPMNs. In patients with PBM, the sphincter of Oddi no longer prevents bidirectional reflux of bile and pancreatic juice. Nonetheless, sphincter of Oddi manometry shows dysfunction in patients with PBM, and sphincterotomy significantly improves their clinical course.23Guelrud M. Morera C. Rodriguez M. et al.Sphincter of Oddi dysfunction in children with recurrent pancreatitis and anomalous pancreaticobiliary union: an etiologic concept.Gastrointest Endosc. 1999; 50: 194-199Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar Further work to correlate biliary anomalies with IPMNs is needed before clinical studies of endoscopic or surgical therapy that are based on these propositions. Because of the bleak outcome of pancreas carcinoma, high morbidity of pancreas surgery, and high cost of intensive surveillance, several approaches are being investigated to assess which pancreatic cysts have malignant potential. Measurement of carcinoembyronic antigen levels and genetic analysis of the juice obtained by fine-needle aspiration are frequently performed.24Brugge W.R. Lewandrowski K. Lee-Lewandrowski E. et al.Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study.Gastroenterology. 2004; 126: 1330-1336Abstract Full Text Full Text PDF PubMed Scopus (1095) Google Scholar, 25Khalid A. Zahid M. Finkelstein S.D. et al.Pancreatic cyst fluid DNA analysis in evaluating pancreatic cysts: a report of the PANDA study.Gastrointest Endosc. 2009; 69: 1095-1102Abstract Full Text Full Text PDF PubMed Scopus (356) Google Scholar The passage of tiny scopes and confocal probes through fine-needle aspiration needles to enable direct visualization and microscopic assessment of the cyst lining is under active investigation.26Konda V.J. Aslanian H.R. Wallace M.B. et al.First assessment of needle-based confocal laser endomicroscopy during EUS-FNA procedures of the pancreas (with videos).Gastrointest Endosc. 2011; 74: 1049-1060Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 27Nakai Y. Iwashita T. Park D.H. et al.Diagnosis of pancreatic cysts: endoscopic ultrasound, through-the-needle confocal laser-induced endomicroscopy and cystoscopy trial (Detect Study).Gastrointest Endosc. 2012; 75: AB145-AB146Abstract Full Text Full Text PDF Google Scholar Nonetheless, careful analysis of cyst appearance, often during the initial radiographic or endosonographic (endoscopic ultrasound) analysis, is the least invasive and most straightforward means to characterize the adverse potential of these lesions. Although cyst size and morphology remain paramount considerations, the appearance of structures “in the neighborhood” of the cyst may harbor clues about future behavior as well as potential treatment. Biliary Findings Assist in Predicting Enlargement of Intraductal Papillary Mucinous Neoplasms of the PancreasClinical Gastroenterology and HepatologyVol. 11Issue 5PreviewThere is controversy over the optimal management strategy for patients with branch-duct type intraductal papillary mucinous neoplasms of the pancreas (BD-IPMNs), precursors to pancreatic cancer. We aimed to identify factors associated with the presence of BD-IPMNs and changes in their diameter. Full-Text PDF